Infections Are Implicated in Prostate Cancer

Viruses in the male genital tract and their effects on the reproductive system. N Dejucq, B Jegou. Microbiol Mol Biol Rev 2001 Jun;65(2):208-231. "In addition to providing an exhaustive account of the data available in these domains, this review focuses attention on the fact that the interface between endocrinology and virology has so far been poorly explored, particularly when major health, social and economical problems are posed."

Meta-analysis of measures of sexual activity and prostate cancer. LK Dennis, DV Dawson. Epidemiology 2002 Jan;13(1):72-79. "The data suggest an elevated relative risk (RR) of prostate cancer among men with a history of sexually transmitted infections. This was observed with both random- and fixed-effects models (RR = 1.4; 95% CI = 1.2-1.7; N = 17 studies; heterogeneity P = 0.14), especially for syphilis (RR = 2.3; 95% CI = 1.3-3.9; N = 6; heterogeneity P = 0.47). Risk of prostate cancer is also associated with increasing frequency of sexual activity (RR = 1.2 for an increase of three times per week; 95% CI = 1.1-1.3; N = 12). However, these studies are heterogeneous (P < 0.001). Increasing number of sexual partners is also associated with prostate cancer (RR = 1.2 for an increase of 20 partners; 95% CI = 1.1-1.3; N = 16; heterogeneity P = 0.11). The data do not support associations with multiple marriages, age at first intercourse, or age at first marriage. These results indicate an association between prostate cancer and sexually transmitted infections, suggesting that infections may represent one mechanism through which prostate cancer develops."

Demonstration of Epstein-Barr virus in carcinomas of various sites. S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo, VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "Seven of 19 carcinomas showed strong EBV reactions in 5–30% of neoplastic nuclei. These cases included all grades of the Gleason classification ranging from well-differentiated adenocarcinomas (Fig. 1i) to hypernephroid and solid tumors. One of 7 carcinomas included foci of high-grade PIN, where convincing EBV reactive nuclei were seen in both basal and luminal cells (Fig. 1j) . All prostate carcinoma samples included foci of benign glandular hyperplasia, 3 of which showed sporadic positive nuclei; 10 normal prostate samples were negative. CD21 was not detected in epithelial cells. Our findings of EBV in prostatic carcinomas are entirely new. In these cases, the presence and possibility of EBV appeared unrelated to the degree of neoplastic differentiation because it was found in the entire range of tumors from those composed of regular glands to poorly differentiated and hypernephroid carcinomas. Interestingly, an architecturally and cytologically distorted carcinoma removed after androgen deprivation therapy showed abundant EBV-reactive cells. Also, in a single case of carcinoma, foci of high-grade PIN, acknowledged to be a precancerous proliferation, showed EBV immunostaining. This apparently low incidence may simply reflect the fact that the blocks containing carcinoma selected for this study were not chosen for the concomitant presence of PIN. Perhaps surprising was the frequent finding of scattered immunoreactive EBV cells in benign glandular hyperplasia. These results suggest that EBV may play a role in clearly proliferative but not necessarily malignant or premalignant lesions. In this context, our findings in the prostate parallel the above-described findings in nonprecancerous epithelial proliferations of the breast and colon. Conversely, the presence of EBV in dysplastic and precancerous proliferations of the prostate and breast underscores that EBV may indeed have an optional role in the development of carcinomas of these sites."

Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. A Zambrano, M Kalantari, A Simoneau, JL Jensen, LP Villareal. Prostate 2002 Dec 1;53(4):263-276. "The paraffin-embedded archival samples gave variable, unsatisfactory results. Results from the fresh frozen samples, however, were consistent and were frequently positive for JCV and less frequent for BK virus DNA. ISH confirmed the presence of JCV DNA in prostatic glandular epithelium."

Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden). O Alexeyev, J Bergh, I Marklund, C Thellenberg-Karlsson, F Wiklund, H Gronberg, A Bergh, F Elgh. Cancer Causes Control 2006 Nov;17(9):1127-1133. 352 patients with benign prostate hyperplasia (BPH) who later developed prostate cancer (n = 171) and matched controls that did not progress to cancer (n = 181). "In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate-Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2), Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77-6.95)."

Adenovirus / SSBP2

Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes. HB Fleisig, NI Orazio, H Liang, AF Tyler, HP Adams, MD Weitzman, L Nagarajan. Oncogene 2007 Jul 19;26(33):4797-4805. "Sequence-specific single-stranded DNA-binding protein 2 (SSBP2) is a candidate tumor suppressor for human acute myelogenous leukemia (AML). Inducible expression of SSBP2 causes growth arrest and partial differentiation in AML cells. Here, we report that the adenoviral oncoprotein E1B55K directly binds to endogenous SSBP2 protein and sequesters it into juxtanuclear bodies in adenovirally transformed human embryonic kidney (HEK) 293 cells.... These data demonstrate that E1B55K targets the candidate leukemia suppressor SSBP2 and suggest that subverting its function may contribute to cell transformation by viral oncoproteins."

ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer. JW Liu, JK Nagpal, W Sun, J Lee, MS Kim, KL Ostrow, S Zhou, C Jeronimo, R Henrique, W Van Criekinge, CS Moon, JA Califano, B Trink, D Sidransky. Clin Cancer Res 2008 Jun 15;14(12):3754-3760. "Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer."

Xenotropic Murine Leukemia Virus-Related Gammaretrovirus (XMRV)

Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. A Urisman, RJ Molinaro, N Fischer, SJ Plummer, G Casey, EA Klein, K Malathi, C Magi-Galluzzi, RR Tubbs, D Ganem, RH Silverman, JL DeRisi. PLoS Pathog 2006 March; 2(3): e25. A subset of patients with familial prostate cancer have a gene defect which is associated with increased susceptibility to certain infections. A high proportion of these patients have been infected with a retrovirus, named XMRV, which is similar to murine leukemia viruses (8/20 vs. 1/66). The Env protein sequence had the highest amino acid identity with the Env protein of an infectious MuLV isolated from a human small cell lung cancer line.

Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. S Kim, N Kim, B Dong, D Boren, SA Lee, J Das Gupta, C Gaughan, EA Klein, C Lee, RH Silverman, SA Chow. J Virol 2008 Oct;82(20):9964-9977. "Balanced chromosome rearrangements, particularly translocations, are strongly associated with distinct tumor entities and may represent an initial event in oncogenesis. The common fragile site is another cancer-associated genomic feature that is frequently altered in non-virus-associated tumors. Both cancer breakpoints and common fragile sites are preferential integration targets for vector DNA, hepatitis B virus, and various DNA viruses, including human papillomavirus, Epstein-Barr virus, simian virus 40, and adeno-associated virus. These integration events may contribute significantly to the development of various types of cancers by disrupting the normal activity of tumor suppressor genes or proto-oncogenes in the vicinity. In the SCID-X1 gene-therapy trial wherein two patients received an MLV-derived vector and subsequently developed leukemia via activation of the LMO2 oncogene, the two integration sites targeted by the MLV-based vector reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Since XMRV integration in DU145 cells does not display a bias for cancer breakpoints and common fragile sites, the high XMRV integration preference seen in tumor samples for genomic regions with the highest frequencies of cancer breakpoints and common fragile sites is striking and likely represents a selection process. The key question of whether these integrated proviruses are an indirect consequence of genomic instability initiated by other genetic lesions or perhaps have a direct role in prostate carcinogenesis awaits further investigations." Integration also occurs in cytoband 16q22.1. "Two other integration sites, one each located in 11q13.4 and 19p13.2, are also in regions where high rates of chromosomal alterations have been observed in breast and prostate cancers."

Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. N Fischer, O Hellwinkel, C Schulz, FK Chun, H Huland, M Aepfelbacher, T Schlomm. J Clin Virol 2008 Nov;43(3):277-283. "Forty percent (8/20) of familial prostate cancer patients homozygous for a mutation in RNase L (R462Q) were positive for XMRV, while the virus was rarely (1/66) detected in familial prostate cancer patients heterozygous for R462Q or carrying the wild type allele... XMRV-specific sequences were detected in one of 105 tissue samples from non-familial prostate cancer patients and from one of 70 tissue samples from men without prostate cancer. The two XMRV-positive patients were wild type or heterozygous for the R462Q mutation and thus carried at least one fully functional RNase L allele."

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. R Schlaberg, DJ Choe, KR Brown, HM Thaker, IR Singh. Proc Natl Acad Sci U S A 2009 Sep 22;106(38):16351-16356. By quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum, XMRV DNA was found in 6% and XMRV protein expression in 23% of 334 consecutive prostate cancers. There was no relation with a common polymorphism in the RNASEL gene.

Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. O Hohn, H Krause, P Barbarotto, L Niederstadt, N Beimforde, J Denner, K Miller, R Kurth, N Bannert. Retrovirology 2009 Oct 16;6:92. 589 prostate tumor samples were all negative for XMRV, either DNA or RNA.

The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. MJ Metzger, CJ Holguin, R Mendoza, AD Miller. J Virol 2010 Feb;84(4):1874-1880. "Here we have used cultured fibroblast and epithelial cell lines to test the hypothesis that XMRV might have direct transforming activity but found only rare transformation events suggestive of indirect transformation, even when the target cells expressed the human Xpr1 cell-entry receptor for XMRV."

Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. BP Danielson, GE Ayala, JT Kimata. J Infect Dis 2010 Nov 15;202(10):1470-1477. "XMRV was detected in 32 (22%) of the 144 patients. Patients were significantly more likely to test positive for XMRV in both tumor and normal tissue rather than either alone (κ = 0.64). A positive result for XMRV was not significantly correlated with the R462Q polymorphism (P = .82) or clinical pathological parameters of prostate cancer, including Gleason score (P = .29)."

Prevalence of human xenotropic murine leukemia virus-related gammaretrovirus (XMRV) in dutch prostate cancer patients. GW Verhaegh, AS de Jong, FP Smit, SA Jannink, WJ Melchers, JA Schalken. Prostate 2011 Mar 1;71(4):415-420. XMRV sequences were detected in 3 out of 74 (4%) prostate cancer specimens. "The number of XMRV containing cells was extremely low (1 in 600-7,000 cells). This was corroborated by the fact that XMRV could not be detected in consecutive tissue sections of the initial XMRV-positive cases."

cast 03-02-12